9-Deoxy-6,9α-epoxymethano-5,6-didehydro-PGF1, amide

ABSTRACT

The present invention relates to novel 9-deoxy-6,9αepoxymethano-5,6-didehydro-PGF 1 , amides, which are useful for inducing a variety of prostacyclin-like pharmacological effects. Accordingly, these compounds are useful pharmacological agents for the same purposes for which prostacyclin is employed.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a divisional application of U.S. Ser. No. 935,392, filed Aug. 21, 1978, now pending issuance as a United States patent; which is a divisional application of U.S. Ser. No. 819,941, filed July 28, 1977, now U.S. Pat. No. 4,124,599; which is a continuation-in-part application of U.S. Ser. No. 725,547, filed Sept. 22, 1976, now abandoned; which is a continuation-in-part application of U.S. Ser. No. 716,771, filed Aug. 23, 1976, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel 9-deoxy-6,9α-epoxymethano-5,6-didehydro-PGF₁, amides, which are useful for inducing a variety of prostacyclin-like pharmacological effects. Accordingly, these compounds are useful pharmacological agents for the same purposes for which prostacyclin is employed.

The essential material constituting a disclosure of the preparation and use of the novel compounds of the present invention is incorporated here by reference from U.S. Pat. No. 4,124,599.

SUMMARY OF THE INVENTION

The present invention particularly provides a 5 E compound of the formula ##STR1## wherein W₁ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, α--CH₂ OH:β--H;

wherein L is

(1) --(CH₂)_(d) --C(R₂)₂,

(2) --CH₂ --O--CH₂ --Y--, or

(3) --CH₂ CH═CH--,

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH_(2L) )₂ --,

wherein Q is oxo, α--H:β--H, α--OH:β--R₈ or α--R₈ :β--OH

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein R₉ is hydrogen, methyl, or ethyl;

wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive; and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof; and a 5 Z compound of the formula ##STR2## wherein W₁ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, α--CH₂ OH:β--H;

wherein L is

(1) --(CH₂)_(d) --C(R₂)₂,

(2) --CH₂ --O--CH₂ --Y--, or

(3) --CH₂ CH═CH--,

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --,

wherein Q is oxo, α--H:β--H, α--OH:β--R₈ or α--R₈ :β--OH

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and

wherein R₉ is hydrogen, methyl, or ethyl;

wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive; and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof.

With regard to the divalent substituents described in the claims, e.g., Q and W₁, these divalent radicals are defined as α--R_(i) :β--R_(j), where R_(i) represents a substituent of the divalent moiety of the alpha configuration with respect to the cyclopentane and R_(j) represents a substituent of the divalent moiety of the beta configuration with respect to the cyclopentane ring. Accordingly, when Q is defined as α--OH:β--R₈, the hydroxy of the Q moiety is in the alpha configuration, i.e., as in prostacyclin, and the R₈ substituent is in the beta configuration. Not all carbon atoms to which such divalent moieties are attached represent asymmetric centers. For example, when both valence bonds are to hydrogen (e.g., W₁ or Q is α--H:β--H), then no asymmetric center is present.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following chemical compound:

(5Z)-9-deoxy-6,9α-epoxymethano-Δ⁵ -17,18-cis-didehydro-PGF₁, amide. 

I claim:
 1. A 5E compound of the formula ##STR3## wherein W₁ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, α--CH₂ OH:β--H;wherein L is (1) --(CH₂)d--C(R₂)₂, (2) --CH₂ --O--CH₂ --Y--, or (3) --CH₂ CH═CH--,wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --, wherein Q is oxo, α--H:β--H, α--OH:β--R₈ or α--R₈ :β--OH wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₉ is hydrogen, methyl, or ethyl; wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive; and wherein X is (1) trans--CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --;including the lower alkanoates thereof.
 2. A 5Z compound of the formula ##STR4## wherein W₁ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, α--CH₂ OH:β--H;wherein L is (1) --(CH₂)_(d) --C(R₂)₂, (2) --CH₂ --O--CH₂ --Y--, or (3) --CH₂ CH═CH--,wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --, wherein Q is oxo, α--H:β--H, α--OH:β--R₈ or α--R₈ :β--OH wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein R₉ is hydrogen, methyl, or ethyl; wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive; and wherein X is (1) trans--CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --;including the lower alkanoates thereof.
 3. (5Z)-9-Deoxy-6, 9α-epoxymethano-Δ⁵ -17,18-cis-didehydro-PGF₁, amide, a compound according to claim
 2. 4. A compound according to claim 1 or 2, wherein W₁ is α--H:β--OH.
 5. A compound according to claim 1 or 2, wherein W₁ is oxo.
 6. A compound according to claim 1 or 2, wherein W₁ is methylene.
 7. A compound according to claim 1 or 2, wherein W₁ is α--H:β--H.
 8. A compound according to claim 1 or 2, wherein W₁ is α--CH₂ OH:β--H.
 9. A compound according to claim 1 or 2, wherein W₁ is α--OH:β--H.
 10. A compound according to claim 9, wherein L is --(CH₂)_(n) --, n being 3, 4, or 5, wherein Q is oxo or α--OH:β--R₈ and wherein R₈ is hydrogen, methyl, or ethyl.
 11. A compound according to claim 10, wherein X is --C.tbd.C--.
 12. A compound according to claim 10, wherein X is --CH₂ CH₂ --.
 13. A compound according to claim 10, wherein X is trans--CH═CH--. 